Summary

Little is known about the neural correlates of tics and associated urges. In the present study, we aimed to explore the neural basis of tics in patients with Tourette syndrome by using event-related functional MRI (fMRI). Ten patients (6 women, 4 men; age: mean ± SD = 31 ± 11.2) were studied while spontaneously exhibiting a variety of motor and vocal tics. On the basis of synchronized video/audio recordings, fMRI activities were analysed 2 s before and at tic onset irrespective of the clinical phenomenology. We identified a brain network of paralimbic areas such as anterior cingulate and insular cortex, supplementary motor area (SMA) and parietal operculum (PO) predominantly activated before tic onset (P < 0.05, corrected for multiple comparisons). In contrast, at the beginning of tic action, significant fMRI activities were found in sensorimotor areas including superior parietal lobule bilaterally and cerebellum. The results of this study indicate that paralimbic and sensory association areas are critically implicated in tic generation, similar to movements triggered internally by unpleasant sensations, as has been shown for pain or itching.

tic

Tourette syndrome

functional MRI

paralimbic areas

Introduction

Tics are abrupt, repetitive stereotyped movements or vocalizations. Tourette syndrome (TS) is the most severe chronic tic disorder, characterized by multiple motor and phonic tics. Co-morbid obsessive compulsive disorder (OCD), attentional deficit hyperactivity disorder (ADHD) and other behavioural disorders are frequently associated (Freeman et al., 2000). When diagnostic criteria are strictly applied, TS is not a rare disorder. Prevalence rates up to 1–2% (Hornse et al., 2001) have been found in school children, and 0.3–0.5% in adults (Stern et al., 2005), although these figures include many mild cases and significantly symptomatic TS seen in clinics is far less common. Tics may be classified as simple or complex. Simple tics are brief and meaningless movements or sounds, involving only individual muscle groups, while complex tics are slower, consisting of coordinated, seemingly meaningful movements or utterances. The present study focuses on simple motor (e.g. eye blinking) and phonic tics (e.g. grunting). Many patients experience an unpleasant feeling of urge before tic onset. This urge is characterized by general psychic tension or by sensory symptoms driving the tic actions, possibly similar to the urge to scratch an itch (Hallett, 2001). Although this trigger of tics is largely involuntary in nature, tic actions per se are under some intentional control. Tics can be voluntarily acted out to bring momentary relief of the uncomfortable sensation, or they can be temporarily suppressed against that urge. Furthermore, tics are sometimes suggestible, and patients may be able to imitate their tics. Tics often look like voluntary ballistic movements and have similar EMG features. Therefore, an important difference seems to be in the way they are triggered (Hallett, 2001). Tics are triggered by the psychic tension or sensory discomfort of the urge; voluntary movements are self-initiated by the poorly understood mental process of conscious will.

Little is known about the neural basis of tic generation and associated urges. Only a few studies have focused on the investigation of tics directly. EEG studies (Obeso et al., 1981; Karp et al., 1996) have shown an absence of the readiness potential (RP) before tics compared with voluntary imitation of tics. While lateral and mesial pre-motor areas are probably most responsible in generating this potential, the findings point to a lack of activity particularly in mesial pre-motor areas, which have been shown to be more likely active with self-paced movements (Deiber et al., 1999; Ikeda et al., 1999; Cunnington et al., 2002). In brief, the studies support the notion that internal triggering of tics and voluntary movements might be different. A previous PET study (Stern et al., 2000) correlated tic intensity with brain activity in a complex network of sensory, motor, paralimbic and subcortical areas. An fMRI study showed that tic suppression was associated with decreased subcortical activation, but increased activation in right caudate and right mid-frontal cortex (Peterson et al., 1998). These effects were inversely correlated with tic severity. These functional neuroimaging studies point to a dysregulation at the basal ganglia and limbic system level involved in tic generation. Studies on baseline metabolism in TS by FDG-PET showed an abnormal limbic–motor coupling compared with normal controls (Jeffries et al., 2002) as well as overactivity of secondary motor areas in earlier studies (Braun et al., 1993; Eidelberg et al., 1997).

There is electrophysiological evidence that the motor system is disinhibited in TS. As assessed by transcranial magnetic stimulation, intracortical inhibition was deficient and cortical silent period shortened in TS patients (Ziemann et al., 1997). Furthermore, there is less habituation for the acoustic startle reflex (Gironell et al., 2000). Hyperexcitability of the motor system might be related to a dysregulation within limbic–motor and corticobasal ganglia circuits, thought to play an important role in the pathophysiology of TS (Berardelli et al., 2003). The development of event-related fMRI allows monitoring of single tics.

The goal of this study was to evaluate commonly activated brain areas during different motor and vocal tics in patients with TS using event-related fMRI. The design of the study incorporates two behavioural conditions: tic generation and tic imitation. Associated fMRI activities were examined at two time points: 2 s before and at event onset. This time window was chosen because preparatory neural activity associated with normal self-generated movements, notably in mesial pre-motor areas, precedes activation of primary motor areas on average by this interval (Ball et al., 1999; Weilke et al., 2001; Hulsmann et al., 2003). On the basis of previous studies, we hypothesized that paralimbic and sensorimotor association cortices are particularly activated during tic generation. Differential activation of individual tics and imitation of those tics may further shed light on the neuroanatomical correlates of tic generation and accompanying urges.

Material and methods

Patients

Twenty-two patients, fulfilling DSM-IV-TR criteria for TS, participated in the study. Preliminary screening of patients was performed in the Human Motor Control Section Outpatient Clinic of NINDS. The study protocol was approved by the Institutional Review Board of NINDS, and informed written consent was obtained from all patients. Patients were selected for the study if they had frequent (on an hourly basis) motor and phonic tics and if these tics were typically simple in nature. Furthermore, patients should be able to imitate their tics. Patients with head or neck tics that could produce substantial head movements were not considered for the study. From 22 originally participating patients, 12 patients had to be excluded for various reasons. Some patients had excessive head movements during the experiment (n = 6). These experiments had been stopped prematurely or the data had to be discarded later owing to resulting motion artefacts. Other patients had too few tics (n = 3) or developed too many or too complex tics (n = 3) during the experiments.

Data from 10 patients (6 women, 4 men; age: mean ± SD = 31 ± 11.2) were included in the final fMRI analysis. Demographic and clinical characteristics of these patients are summarized in Table 1. Tics were assessed with the Yale Global Tic Severity Scale (YGTSS). Four patients had a co-morbid OCD and two patients ADHD, as assessed by the Structured Clinical Interview for DSM-IV (SCID). Nine patients were drug-free; one patient was taking amitriptyline 25 mg and aripiprazole 2 mg a day, which was stopped 24 h before the study. The principal tics involved various facial and body movements as well as simple sounds. The patients were asked to estimate the frequency of urge associated with tics (with <25%, 25–50%, 50–75% or with >75% of tics), many reporting a frequency in the middle range (25–50 and 50–75% of tics). Most patients experienced the urges within a few seconds before the tics and when attempting to suppress them.

Functional MRI (fMRI) experiments

Behavioural data recordings and analysis

The patients underwent four fMRI scanning sessions, each lasting 8 min and 20 s. Within two sessions the patients were instructed to relax and to let their tics emerge without any effort to induce or suppress them. In two other sessions, which were randomly intermixed, the patients were asked to imitate the tics when they did not feel the urge to tic. The patients were instructed to mimic their tics as closely as possible in random intervals of 10–20 s. Facial and body movements were monitored with two digital video cameras, positioned outside the scanner room. Vocal tics were recorded using an MRI-compatible sound-recording device. The video/audio recordings were synchronized with the MR scanner. Three researchers assessed the audio and video recordings (S.B., A.G. and S.M.). In the tic generation and imitation conditions, the events were considered for analysis when two of the authors agreed on timing and nature of the events. Discrimination between tics and imitation were judged qualitatively on features such as promptness, forcefulness, spontaneity and stereotypy of movements. While tics appeared to be more rapid, vigorous and closely resembling each other, imitations appeared more purposeful, and were slower and varied in their manifestation.

Imaging data analysis

Tic- and imitation-related increases in BOLD signal were analysed for each patient on a Linux workstation (Red Hat 8.0) using SPM2b software (http://www.fil.ion.ucl.ac.uk/spm) implemented in MATLAB 6.51SP1 (Math-Works, Natick, MA). DICOM images were converted to Analyze format using the software DCMTK-DICOM Toolkit (http://dicom.offis.de/dcmtk). After slice time correction, functional images were spatially realigned to the first image of each session for head motion correction. Head movements as assessed by the realignment parameters were tolerated up to 2 mm. Functional images were spatially normalized to the default EPI template proposed in SPM2 and resampled into voxels that were 2 × 2 × 2 mm in size. Images were then smoothed with a Gaussian filter of 8 mm full width at half maximum (FWHM) to minimize noise and residual differences in gyral anatomy.

Both first- and second-level analyses were performed. In the first level, data were analysed for each patient separately on a voxel-by-voxel basis using the principles of the general linear model (Friston et al., 1995). Each individual design matrix included pooled data from all four experimental sessions. Timing of onsets of tics or imitations was determined from the video and audio recordings based on criteria described above. Event times were rounded to the next full second. Ambiguous events were modelled out as regressors of no interest. Column vectors representing time at tic and imitation onset, as well as tic and 2 s before imitation onset were convolved with a canonical haemodynamic response function (HRF) and its temporal derivatives to create regressors, which were fitted to the individual fMRI time series. Variance from head motion has been considered in the statistical design by adding six regressors as covariates of no interest, containing rotation and translation parameters from spatial realignment. A high-pass filter of 128 s was used to remove low-frequency noise.

Two sets of contrast images were created from analyses testing for an increase in brain activity 2 s before tic onset and at tic onset. These contrast images were used in two separate second-level random effects analyses. Random effects analysis allows inferences on a population level by correcting for inter-individual variability, which makes it unlikely that outliers determine the results. Statistical threshold was set to P < 0.05, corrected for multiple comparison across the whole brain volume using false discovery rate (FDR) (Genovese et al., 2002). Locations of activated areas for different conditions were displayed by superimposing them on a high-resolution 3D T1-weighted MRI brain scan normalized according to the Talairach standard space (Talairach and Tournoux, 1988). Anatomical localization of activations was determined from 3D coordinates in Talairach space obtained by using the mni2tal tool.

Results

Behavioural observations during tic sessions

The registered tics included eye blinking, nose twitching, grimacing, abdominal tensing, foot, wrist and arm stretching, coughing, snoring, grunting and barking. On average, a total of 30–80 tics were recorded in each patient across the two tic sessions occurring at random intervals of a few seconds up to minutes. Most of the tics were simple in nature, although some of them appeared more dystonic, like grimacing or arm stretching tics. Some of the tics occurred simultaneously or in brief trains, modelled as single events in the statistical design.

fMRI data

A major goal of the present study was to use event-related fMRI to measure changes in brain activity 2 s before motor and vocal tic onset and at tic onset. An overview of the distributed cortical activations resulting from second-level group analysis (n = 10) at the two points in time is depicted in Fig. 1. Before tic onset (indicated in red), the most significant fMRI activities were found in medial pre-motor areas including the supplementary motor area (SMA), as well as scattered in lateral pre-motor areas. Strong activations were also observed in parietal operculum (PO), bilaterally. At tic onset (green) much less activation was found in these regions (overlap in yellow), whereas a greater extent of BOLD signal was seen in sensorimotor areas and cerebellum. In addition, superior parietal lobules (SPL) bilaterally and the left dorsolateral pre-frontal cortex (DLPFC) were exclusively activated at the beginning of tics.

Superior and lateral overviews of significant fMRI activations (P < 0.05, corrected for multiple comparisons) rendered on template hemispheres before (red) and at tic onset (green). Before tic onset significant activations were found in mesial and lateral pre-motor areas, while at tic onset sensorimotor including SPL activations were observed.

Exact Talairach coordinates, converted form MNI using the mni2tal tool, of peak activations (maxima within clusters >50 contiguous voxels) are given in Tables 2 and 3, for both points in time separately. The statistical threshold was set to P < 0.05, corrected for multiple comparisons. The strength of activations at the two time points was derived from the Z score.

Activation of paralimbic areas and SMA during tic generation

Details of fMRI activation patterns during tic generation (before tic onset), particularly of paralimbic areas such as anterior cingulate cortex (ACC) and insula as well as SMA, are depicted in Fig. 2. As shown on axial views (Fig. 2A) prior to tic onset, strong fMRI activations were found in the insular region (Brodmann area, BA 13) and posterior putamen, bilaterally, which were clearly less marked at tic onset. In addition, as depicted on coronal sections (Fig. 2B), in addition to the insular and putaminal activities, strong fMRI signals could be detected in ACC (BA 24) and SMA (BA 6) bilaterally compared with tic onset. Correspondingly, left parasagittal (Fig. 2C) and sagittal sections (Fig. 2D) further illustrate the extent of activations in ACC and SMA before tic appearance, which was considerably diminished with the beginning of tic movements. In contrast, the area of activity in cerebellum including vermis was larger at tic onset than before. Finally, at tic onset, significant BOLD signals could be detected in substantia nigra bilaterally not yet present before (not shown).

Imitation of tics

The assessment of differential activation between tics and imitation of tics proved to be difficult for two major experimental reasons. First, imitation of tics in a number of patients triggered unacceptable head movements producing significant motion artefacts. Secondly, the discrimination of imitations from real tics based on video analysis was not always straightforward. Ambiguous events had to be modelled out, thereby significantly reducing the number of measurable events. Therefore, we did not succeed in collecting enough data to be able to analyse it with sufficient statistical power.

Discussion

Only limited data are available on the pathophysiology of individual tics in TS. Functional neuroimaging studies have been restricted to EEG experiments with low spatial resolution (Obeso et al., 1981; Karp et al., 1996) and a PET study with low temporal resolution (Stern et al., 2000). The development of event-related fMRI, as employed in the present study, allows exploring neural substrates of tics by combining a better temporal with an excellent spatial resolution. We identified a set of paralimbic brain areas (ACC and insular region) and PO activated before manifestation of single motor and phonic tics. Thus, along with PO, ACC and insular cortex appear to constitute a distinct neural network for tic generation. Our findings are consistent with a previous [15O] H2O PET study that correlated the occurrence of tics in TS (Stern et al., 2000) with a complex set of brain areas including mesial pre-motor cortices, left dorsolateral-rostral pre-frontal cortex, inferior parietal cortex bilaterally, basal ganglia and insular region. Furthermore, a particular involvement of insula, cerebellum, SMA and ACC in tic generation has also been found in a recent [15O] H2O PET study at the Human Motor Control Section (Lerner A., Bagic A., Boudreau E., Hanakawa T., Pagan F., Mari Z., et al., unpublished data).

There is some analogy between tics and itching. Both are associated with a ‘need to move’. There may even be some similarity to movements triggered by pain. In numerous functional neuroimaging studies, unpleasant feelings associated with itch and urge to scratch or pain have been shown to implicate a network of ACC, insula, thalamus and PO (Hsieh et al., 1994; Tolle et al., 1999; Kwan et al., 2000; Ostrowsky et al., 2002; Mochizuki et al., 2003; Derbyshire et al., 2004; Lu et al., 2004), similar to the findings of the present study on tic generation. Furthermore, electrical stimulation of SMA can produce a sense of urge to move (Fried, 1991). Interestingly, vague visceral sensations, which might accompany urges, have been shown to activate PO, ACC and insular region (Aziz et al., 1997). It is noteworthy that direct electrical stimulation of insular cortex in patients with epilepsy frequently elicits unpleasant somato- and viscerosensory sensations in various facial, limb and pharyngolaryngeal areas (Isnard et al., 2004). Electrical stimulation of PO in the same study produced similar somatosensory experiences, although somatotopically more restricted. The insular region has rich reciprocal connectivity with the PO, ACC, and motor regions (Augustine, 1996). It is, therefore, at the interface of limbic and motor system, well suited for integrating somato- and viscerosensory sensations, accompanying emotional reactions and motor responses. In line with the accumulating experimental, clinical and anatomical data, the strong fMRI activation of paralimbic areas and PO preceding tics in the present study supports the role of this network as a potential substrate for the uncomfortable feelings associated with premonitory urges of tics. The urge to move is also characteristic for compulsive behaviour, which has clinical overlap with tics. Particularly complex tics are sometimes difficult to differentiate from compulsive acts. This relationship is reflected by the findings of functional neuroimaging studies that demonstrated that ACC is specifically involved in the pathophysiology and mediation of OCD symptoms (Rauch et al., 1994; Adler et al., 2000).

ACC, together with SMA, is also a mesial pre-motor association area that has been shown to play an important role in driving and initiating voluntary movements. Accordingly, bilateral lesions of these structures cause severe deficits in motor activation, called akinetic mutism (Amyes and Nielsen, 1953; Barris and Schuman, 1953; Laplane et al., 1981; Nemeth et al., 1988). Furthermore, the impairment of self-initiated movements in Parkinson's disease has been shown to be related to SMA underactivation (Jahanshahi et al., 1995). Conversely, tics can be viewed as excess of movement and electrical stimulation of mesial pre-motor areas produces various motor responses including clonic and tonic contractions as well as more complex automatism in the face and upper and lower limbs similar to tics (Talairach et al., 1973; Bancaud et al., 1976; Lim et al., 1994). Interestingly, sensory symptoms also have been elicited by electrical stimulation in this region (Lim et al., 1994). ACC and SMA are major mesocortical targets of dopaminergic projections that arise from mid-brain structures such as substantia nigra and ventral tegmental area (Lindvall et al., 1974; Le Moal and Simon, 1991). Involvement of these systems and basal ganglia can be further assumed on the basis of the efficacy of anti-dopaminergic treatment on tics in TS patients. Hence, clinical, anatomical and neurochemical data suggest that tics in TS may be generated by excessive mesocortical discharges. Our findings, including the activation of substantia nigra at tic onset, support this view.

While sensory function is generally considered to be intact in TS, there is clinical and electrophysiological evidence that sensorimotor integration or gating may be abnormal in these patients. Clinically, sensorimotor dysfunction is obvious by the various experiences of local or general discomfort that drive tics. Sensorimotor integration can be assessed neurophysiologically, for example, by pre-pulse inhibition of blink reflex. Two studies point to a defective pre-pulse inhibition in patients with TS, indicating that the ability of sensory stimuli to inhibit motor behaviour is diminished (Castellanos et al., 1996; Swerdlow et al., 2001). The involvement of sensory areas during tic generation as demonstrated in our study clearly underscores the sensorimotor nature of tics. The significance of PO has already been discussed (see above). The bilateral activation of SPL at tic onset may account for its role as part of parietofrontal circuitry in sensorimotor integration and motor attention. Specifically, activation of SPL may be interpreted as an expression of a certain self-awareness of tics (MacDonald and Paus, 2003). Interestingly, the functional connectivity of SPL to motor and limbic areas has been shown to be stronger in TS patients compared with normal controls (Jeffries et al., 2002). On the basis of these abnormal connectivities it was speculated that SPL could mediate limbic-motor interactions (Jeffries et al., 2002).

Some limitations of this study must be considered. First, there was a substantial heterogeneity of recorded tics, which may be a confounding factor. However, we were primarily interested in detecting a common neural substrate underlying tics regardless of their phenomenological appearance. This bias should be less important for fMRI activities preceding tic onset. Another concern in this study was the influence of tic suppression. Patients were aware that head motion should be avoided; therefore, contamination by suppression cannot be excluded. However, we do not think that suppression was a major factor in the selected patients, at least not in the tic sessions. Most patients were able to relax in the scanner. Furthermore, although right ACC was more activated than left, other areas associated with suppression of tics (Peterson et al., 1998) such as right mid-frontal cortex were not activated.

Another question that arises from this study is whether mimicking of tics by TS patients is an appropriate behavioural control for tics. As pointed out in the results, we were not able to collect enough data on imitation to satisfactorily analyse it. On the basis of the video analysis and reports of patients, ‘contamination’ of imitations by real tics was a problem. Tics are often suggestible; even thinking of tics can provoke tics. This fact could be exploited in the tic sessions, but was unwanted in the imitation runs. In some patients the imitation of tics was more demanding and produced head movements disproportionately. Other patients reported that although the task to imitate tics suppressed real tics, the imitation of tics could still evoke sensory experiences associated with real tics. Therefore, in addition to some uncertainty of the video analysis, the boundaries between real tics and their imitation might be blurred. Another issue with respect to mimicking was the fluctuating and spontaneous nature of tics. In the confined and artificial environment of the scanner, several types of tics appeared that were less predominant before the experiment. This latent unpredictability made the instruction of patients to imitate the tics that they had in the scanner sometimes difficult. There is evidence from behavioural studies that in TS patients the control of voluntary movements is by itself abnormal. TS patients showed a slowed reaction time (Shucard et al., 1997). They are more dependent on advance information, and reaction time improves with it (Georgiou et al., 1995b). The patients have difficulties with spatially incongruent stimulus–response configurations (Simon effect) (Georgiou et al., 1995a) and showed an abnormal grip force behaviour (Nowak et al., 2005). Lastly, fMRI studies demonstrated that abnormal motor control was associated with overactivity in secondary motor areas (Biswal et al., 1998; Serrien et al., 2002). Therefore, mimicking of tics might not be an adequate control because ‘normal’ movements in TS patients are probably not normal per se.

Conclusion

Activation of paralimbic networks involving ACC and insular cortex prior to tic onset, as found in this event-related fMRI study, is consistent with the notion of a limbic overdrive of the motor system underlying the pathophysiology of tic generation. Furthermore, together with significant activations of sensory areas, notably PO, these regions appear to be particularly implicated in movements triggered internally by unpleasant or emotional sensations, as shown in functional neuroimaging studies of pain or itching. Future studies may clarify whether subtypes of tics are generated differentially in these brain networks. Also, contrasting real tics in TS patients with mimicked tics by normal volunteers may be needed to further elucidate differences between the neural basis of tics and voluntary movements.